Glycolysis

Overview

Glycolysis is a metabolic pathway that occurs in the cytoplasm of cells and is the initial step in glucose metabolism. It involves the breakdown of glucose into two molecules of pyruvate, generating a small amount of ATP and reducing equivalents. The process consists of several enzymatic reactions, including phosphorylation and rearrangement steps. Glycolysis serves as an important source of energy for cells and is a fundamental process in both aerobic and anaerobic respiration. It plays a crucial role in various physiological and pathological conditions, making it a key focus in the study of metabolism and biochemistry.

Function

• • generation of ATP from glucose via substrate-level phosphorylation (as opposed to oxidative phosphorylation)
    • used by all cells
      • with O₂
        • pyruvate enters citric acid cycle (after being created in glycolysis)
        • NAD+ regenerated via oxidative phosphorylation
      • without O₂
        • pyruvate cannot enter citric acid cycle after glycolysis
        • NAD+ must be regenerated via conversion of pyruvate to lactate
          • catalyzed by lactate dehydrogenase
    • only source of energy for RBCs
  • generation of intermediates for other pathways 
    • 1,3-BPG
      • intermediate of glycolysis
      • can be converted to 2,3-DPG
        • modifies the hemoglobin-O₂ binding curve
          • binds HbA and ↓ binding affinity of O₂
          • a compensatory mechanism for ↓pO₂

Pathway

• • in cytoplasm
  • irreversible
  • net reaction
    • glucose + 2P_i + 2 ADP + 2 NAD⁺ → 2 pyruvate + 2 ATP + 2 NADH + 2H⁺ + 2 H₂O
• Important enzymes 
  • hexokinase – converts glucose into glucose-6-phosphate allowing “trapping” inside cell
    • distribution
      • widely present in most body tissues
        • allows trapping of glucose at all blood glucose levels
    • kinetics
      • high affinity → low K_m
      • low capacity → low V_max
    • regulation
      • feedback inhibited by glucose-6-phosphate
  • glucokinase (hexokinase IV)
    • distribution
      • liver
      • β cells of pancreas
        • uses as a means to measure blood glucose and release insulin accordingly
        • mutated in the monogenenic, autosomal dominant form of diabetes called Maturity Onset Diabetes of the Young type 2 (MODY2)
    • kinetics
      • low affinity → high K_m
      • high capacity → high V_max
    • regulation
      • induced by insulin (to store glucose in liver after a meal)
      • no direct feedback inhibition
  • phosphofructokinase-1
    • rate-limiting step
    • inhibited by ATP, citrate
    • stimulated by AMP, fructose-2,6-bisphosphate
      • fructose 2,6-bisphosphate synthesized by phosphofructokinase-2
  • pyruvate kinase
    • catalyzes substrate-level phosphorylation
    • inhibited by ATP, alanine
    • activated by fructose-1,6-bisphosphate
• Hormonal regulation
  • fasting state
    • ↑ glucagon → ↑ cAMP → ↑ protein kinase A → ↑ FBPase-2, ↓ PFK-2
  • fed state
• ↑ insulin → ↓ cAMP → ↓ protein kinase A → ↓ FBPase-2, ↑ PFK-2

Disorders of Glycolysis

• Pyruvate kinase deficiency
  • AR (most commonly)
  • pathophysiology
    • ↓ ATP generation
      • inability to maintain Na+/K+ ATPase leads to
        • RBC swelling
        • RBC lysis
    • back up of glycolysis
      • ↑ 2,3-BPG and other glycolytic intermediates
  • presentation
    • chronic hemolysis
    • ↓ O₂ affinity for HbA
      • due to ↑ 2,3-BPG
    • no Heinz bodies
• unlike glucose 6-phosphate dehydrogenase deficiency

Studies

Glycolysis has been extensively studied and is a well-established topic in the field of biochemistry and cellular metabolism. Numerous research studies have been conducted to investigate various aspects of glycolysis, including its regulation, enzymatic reactions, and functional implications. Here are a few examples of notable studies related to glycolysis:

1. “Regulation of glycolytic flux in cancer cells” (Vander Heiden et al., 2009): This study explored the dysregulated glycolytic metabolism observed in cancer cells, known as the Warburg effect. It investigated the molecular mechanisms underlying the increased glycolytic flux in cancer cells and its implications for tumor growth and survival.
2. “Metabolic regulation by the mitochondrial pyruvate carrier” (Bricker et al., 2012): This study focused on the role of the mitochondrial pyruvate carrier (MPC) in controlling glycolysis and mitochondrial metabolism. It demonstrated the importance of MPC in regulating glucose utilization and oxidative phosphorylation, providing insights into the coordination of glycolysis with other metabolic pathways.
3. “Glycolysis inhibition for anticancer treatment” (Chen et al., 2014): This study explored the potential of targeting glycolysis as a therapeutic strategy for cancer treatment. It investigated the effects of inhibiting glycolysis on tumor cell growth, survival, and response to chemotherapy, highlighting the potential of glycolytic inhibitors as anticancer agents.
4. “Glycolysis and cancer metabolism” (Liberti and Locasale, 2016): This review article discussed the intricate relationship between glycolysis and cancer metabolism. It provided an overview of the altered glycolytic pathways in cancer cells and their functional implications, emphasizing the therapeutic opportunities for targeting glycolysis in cancer treatment.

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